Glaucoma, a pathologic state in which intraocular pressure exceeding the normal range of 10-20 mmHg results in eyesight disorder, is among the intractable ophthalmopathies. Recently, the incidence of low tension glaucoma has increased. Low tension glaucoma, occurs when intraocular pressure is less than 21 mmHg, which reduces the field of vision and impairs ocular blood flow. The current therapy for glaucoma, including low tension glaucoma is to lower intraocular pressure. For glaucoma chemotherapy, choline agonists, represented by pilocarpine, and anti-choline esterase agents have long been used as eyedrops. These drugs, however, cause severe side effects such as iridic cystoma, iris synechia, cataract and retinal detachment when used in long-term continuous administration, as well as a sensation of darkness due to mydriasis, eye injection and other symptoms.
Although sympathetic nerve agonists such as epinephrine and dipivefrine have been used for their ocular hypotensive action, their use is limited to open-angle glaucoma, and can cause mydriasis, blepharitis and conjunctival pigmentation and systemic symptoms such as increased heart rate and hypertension.
In recent years, .beta.-blockers such as timolol, pindolol and carteolol have been widely used, since they are advantageous in that their instillation suppresses aqueous humor production to lower ocular tension, without acting on the pupil. These drugs, however, tend to cause local symptoms such as feelings of eye dryness, allergic blepharitis and superficial keratitis.
The only group of ocular hypotensive agents that can be used systemically in long-term continuous administration is carbonic acid dehydrogenase inhibitors such as acetazolamide and metazolamide, but these can cause gastrointestinal disorder, ureteroliths and electrolytic anomalies.
In recent years, angiotensin-converting enzyme inhibitors (e.g., Japanese Published unexamined patent application (Kokai tokkyo koho) Nos. 21614/1984, 130816/1984, 209527/1985, 10553/1986, 203665/1988 and 218612/1990), which inhibit the renin-angiotensin system involved in blood pressure regulation, have been reported as useful glaucoma remedies [J. Ocular Pharmacol., 3, 295-307 (1987); Am. J. Ophthalmol., 105, 674-677 (1988)], but none have seen practical application.
Compounds exhibiting angiotensin II antagonistic action are known to serve as therapeutic agents for circulatory diseases such as hypertension, heart diseases (heart hypertrophy, heart failure, myocardial infarction etc.), cerebral stroke and nephritis. Concerning their mechanism of action, inhibition of binding to anglotensin II receptors, a potent vasoconstrictor, has been suggested. Japanese Published unexamined application (kokai tokkyo koho) Nos. 63264/1991, 27362/1991 and 184976/1991 state that angiotensin II antagonists can be used to treat glaucoma.
As stated above, there is not a satisfactory drug offering efficient ocular tension reduction with low side effects.